Targeted Protein Degradation: PROTACs, Molecular Glues, and the Future of Drug Discovery

The ability to selectively eliminate pathogenic proteins rather than merely inhibit their activity has redefined contemporary drug discovery, positioning targeted protein degradation (TPD) as one of the most significant advances in chemical biology and precision therapeutics.By harnessing endogenous protein quality-control machinery, TPD offers a catalytic and event-driven pharmacological strategy capable of addressing limitations associated with conventional occupancydriven inhibitors, including poor target selectivity, transient target engagement, acquired resistance, and the inaccessibility of many disease-relevant proteins.Among the expanding repertoire of degrader technologies, proteolysis-targeting chimeras (PROTACs) and molecular glues have emerged as the most mature and clinically advanced platforms, each employing distinct mechanisms to recruit E3 ubiquitin ligases and direct selective protein degradation.Their rapid evolution has been driven by breakthroughs in structural biology, medicinal chemistry, computational modeling, and artificial intelligence, enabling the rational design of degraders with enhanced potency, selectivity, and pharmacokinetic performance.Beyond oncology, these technologies are increasingly being explored for neurological, inflammatory, infectious, and rare genetic disorders, underscoring their broad therapeutic potential.Nevertheless, challenges related to E3 ligase diversity, tissue specificity, resistance mechanisms, safety, and clinical translation continue to influence their successful implementation.This review critically examines the molecular foundations, design principles, therapeutic applications, and clinical progress of PROTACs and molecular glues while integrating emerging targeted degradation platforms and technological innovations.Furthermore, it discusses the opportunities and unresolved challenges that will shape the next generation of degrader therapeutics and their transformative role in the future of precision drug discovery.